Cyclopentanophenanthrene compounds and process



United States Patent "ice 3,102,892 CYCLOPENTANOPHENANTHRENE COMPOUNDSAND PROCESS John A. Zderic, Mexico City, Mexico, assignor, by mesnelassignments, to Syntex Corporation, a corporation of anama No Drawing.Filed Feb. 6, 1961, Ser. No. 87,114 i 23 Claims. (Cl. 260--343.2)

The present invention relates to novel cyclopentanophenanthrenecompounds and to a process for the production thereof.

More particularly the present invention relates to13,17a,21-trihydroxy-3,20 diketo 11,13 seco A pregnen-ll-oic acid11,13-lactone, to the C-1,2 dehydro derivative thereof as well as to theC21 esters of said compounds.

The novel compounds of the present invention which are potent corticalhormones possessing anti-inflammatory, glycogenic, thymolytic,*catabolic, anti-estrogenic, anti androgenic and anti-gonadotrophicactivities are reph@ OHC\ 0 CH0 I 3,102,892 Patented Sept. 3, 1963 2resented by the following formula:

CHQOR 0=o In the above formula Z represents a double bond or a saturatedlinkage between 0-1 and C2 and R represents hydrogen or the acyl radicalof a hydrocarbon carboxylic acid of less than 12 carbon atoms which maybe saturated or unsaturated, of straight, branched, cyclic orcyclic-aliphatic chain, aromatic and maybe substituted by functional'groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxycontaining up to 8 carbon atoms, amino or halogen. Typical ester groupsare the acetate, propionate, enanthate, caproate, benzoate,trimethylacetate, phenoxyacetate, t-butylacetate,cyclopen'tylpropionate, aminoacetate and fl chloropropionate.

The novel compounds of the present invention are prepared by a processillustrated by the following equation:

H X -i 03,

OHC

HOOC

In the above formula R and Z have the same meaning as previously setforth; R represents the acyl radical of a hydrocarbon carboxylic acid ofthe type mentioned previously and is preferablythe acetyl radical. U Inpracticing the process outlined above the starting compound 11,12 seco 5a-22a-spirostan-313-ol-11,12-dial (I) is prepared by oxidizing11,8,12fi-dihydroxy-tigogenin with lead tetraacetate in an inert solventsuch as benzene. 'I he dialdehyde (I) is esterified at C-3 by treatmentwith acetic anhydride in pyridine and the thus formed C-3 acetate isoxidized with 8 N chromic acid to furnish Sfi-acet-oxy-lZ-aldehydo 11,12seco 5a,22ec spirostan- 11-oic acid (II). Upon reaction withdiazomethane, the methyl ester of the latter acid is formed which isthen subjected to a Baeyer-Villiger reaction using, for example,perbenzoic acid, to form the methyl ester of Bit-acetoxy-11,l3-seco5a,22a-spirostan-13-ol-a11-oic acid 13-form-ate (III). Theformate "and ester groups are hydrolyzed by alkali treatment and uponsubsequent acid treatment, there is formed the lactone, namely3fl,13-dihydroxy-11,13-seco- 5m,22a-spirostan-1iloic acid 11,-l3-lactone(IV). Degradation of the spiroketal side chain is then etiected byconventional procedure as by reaction with acetic anhydride at about200, oxidation of the resulting pseudo compound to the diosone andalkaline hydrolysis and acetylation of the latter thus forming3fl,13-dihydroxy-20-keto-11,13-seco- A-5a-pregnen-1l-oic-acid-l1,13-lactone acetate (V).

For introduction of the hydroxyl group at C-17oc, the 16,17-double bondis first epox-idized, prefenably by reaction with t-butylhydroper-oxideto form the 16a,17aepoxide of V; the epoxide ring is then opened bytreatment with hydrogen bromide and the resulting 1613-bromo-17a-hydroxy compound is reductively debrominated as by refluxingwith Raney nickel to form 3,8,13,l7a-trihydroxy-20-keto-11,13-seco-5a-pregnan-11-oic acid 11,13-lactone3-acetate (VI; R=acetate). ment with acid the 3l3-acetate group istransformed int the Bfl-hydroXygroup (VI: R=hydrogen).

For introduction of a hydroxyl group at -21 the latter compound ismonobrominated and there is formed 21- bromo 35,13,170 trihydroxy 20keto-11,13-seco-apregnan-ll-oic acid 11,13-lactone which is thenacetolysed in a conventional manner, preferably with previoussubstitution of iodine for bromine, to thus form 3fi,13,17oc,2l-tetrahydroxy-ZO-keto-l1,13-seco 5a pregnan-ll-oic acid11,13-lactoue-21-acetate (VII: R=acetate). Upon oxidation of the lattercompound with 8N chromic acid there is formed13,17,21-trihydroxy-3,20-diketo-11,13-

Up on treatseco-5a-pre'gnan-11-oic acid 11,13 lactone 21-acetate. For

introduction of unsaturation in ring A, the latter compound isdibrominated at C-Z and C-4 and then either dehydrobrominated as bytreatment with calcium carbonate in dimethylformamide ordimethylacetamide to produce 13,17a,21trihydroxy-3,20-diketo-11,13-lactone- A pregn'adien 11 oic acid 11,13lactone 21-acetate (VIII: Z=double bond) or dehydrobrominatedselectively as by heating with an alkali metal iodide followed byreductive dehalogenation' to yield the zi -compound, that is, 13,17a,21trihydroxy 3,20 diketo 11,13- seco A pregnen 11 oic acid 11,13-lactone2.1-acetate (VIII: Z saturated linkage). The latter compound can (VII)also be formed by oxidation of the previously mentioned 13,17a,21trihydroxy 3,20 diketo-l1,13-seco-5u-pregnan-ll-oic acid 11,13-lactone21-acetate with selenium dioxide or by oxidation ofl3,17a,21-trihydroxy-3,20- di-keto-l1,13-seco-A -pregnen-11-oic acid11,13 -lactone- 21-acetate (VIII: Z=saturated linkage).

Upon hydrolysis as by reaction with methanolic perchioric acid, theacetoxy group at 0-21 is converted into the free 0-21 hydroxy compoundwhich can then be reacylated with other hydrocarbon carboxylic acids of'the type mentioned-previously.

The following examples serve to illustrate but are not intended to limitthe invention:

Example I To a mixture of 8.1 g. of -11,8,12B-dihydroxy-tigogenin, 1.4liters of glacial acetic acid and 2.1 liters of thiophenefree benzene,121 g. of lead tetraacetate were added and the mixture was stirred atroom temperature for 5 minutes. 2 liters of water, containing 1 kg. ofsodium acetate and 40 g. of sodium iodide were added, the color wasdischarged by addition of 800ml. of saturated aqueous sodium thiosulfatesolution and the product extracted twice, using each time 2 liters ofethyl acetate. The pooled extracts were washed with aqueous sodiumbicarbonate and water, dried over anhydrous sodium sulfate andevaporated to dryness. The residue was crystallized from a mixture of600 ml. of methanol and 125 ml. of water. 'I hus 75.2 g. of11,l2-seco-22a-allospirostan- 3,8-ol-l1,l2-d-ial were obtained; M.P.146-147" C.; [a1 -72 (chloroform).

The above compound was reacted with 75 ml. of acetic anhydride in 400ml. of pyridine, at room temperature and was allowed to stand overnight.The mixture was then poured into water, heated for 1 hour on asteambath', cooled and the solid was collected by filtration, washedconsecutively with diluted hydrochloric acid, aqueous sodium bicarbonateand with water, dried and crystallized from acetone-hexane. Thus11,12-5600-22ocall'ospirostan-3fl ol 11,12 dial acetate was obtained;M.P. 152-154"; [a] 56" (chloroform).

55 g. of the foregoing compound in 1000 ml. of awe tone were treatedwith 7.8 ml. of 8 N chromic acid, preparedin dilute sulfuric acid, underan atmosphere of nitrogen and at room temperature for 35 minutes. Themixture was then diluted with water, the product extracted with ethylacetate, the extract water-washed, dried over anhydrous sodium sulfateand evaporated to dryness. Crystallization from acetone-hexane gave 35-acetoxy-+12-aldehy-do-1l,l2-seco-22a allospirostan 11 oic acid; M.P. 170172; [ab -61 (chloroform).

By treatment of the foregoing acid with an ethereal solution ofdiazomethane in the conventional manner, the methyl ester of the acidwas produced; M.P. 153- 155"; [0th, 65 (chloroform);

To 660 ml. of 0.5 N ethereal solution of perbenzoic acid were added 44ml. of acetic acid containing 44 g. of

the methyl ester of 3p-acetoxy-12-aldehydo-11,12-secowater, dried overanhydrous sodium sulfate and evaporated to dryness, leaving 48 g. ofneutral material. This, in its turn, was refluxed with 680 ml. of 5%methanolic potassium hydroxide, under an atmosphere of nitrogen for 4hours. At the end of this period the mixture was extracted with ethylacetate; the aqueous phase was acidified with dilute hydrochloric acidand left overnight at room temperature. The product was then extracted,repeated with ethyl acetate. The cooled extracts were water-washed,dried over anhydrous sodium sulfate and the solvent was evaporated. Theresidue crystallized from ether-hexane; thus35,l3-dihydroxy-l1,13-seco-5a, 22a-spirostan-11-oic acid-11,13 lactonewas obtained; M.P. 2741-273 [(21 24 (chloroform). 40 g. of the foregoingcompound were heated with 200 m1. of acetic anhydride in a sealed tubeat 200 C. for 55 minutes. The mixture was then cooled, the excess ofanhydride was hydrolyzed by the addition of 50 ml. of water; there werethen added g. of chromium trioxide in 250 ml. of 80% acetic acid, littleby little, while stirring and at about 15 C. Stirring was continued for3 hours at room temperature, the mixture was then diluted with water andthe product extracted with ether. The extract was washed with water,dried over anhydrous sodium sulfate and the ether was evaporated. Theresidue was mixed with 2 liters of aqueous 60% acetone containing 20 g.of potassium hydroxide, and refluxed for 5 hours. At the end of thistime, the liquid was concentrated to small volume at reduced pressure,then diluted with 100 m1. of water, acidified with concentratedhydrochloric acid and stirred at room temperature overnight. It was thenextracted with ether, the extract was water-washed, dried over anhydroussodium sulfate and evaporated. The residue was treated with 40 g. ofacetic anhydride in 200 ml. of pyridine at room temperature and thernixture was allowed to stand overnight. It was then diluted with 1liter of water, the solid collected by filtration, watenwashed, driedand crystallized from acetone-hexane. Thus3fi-acetoxy-13-hydroxy-20-keto 111,13 seco- A-Sa-Pregnen-1'1-oic-acid-11,13-laotone was obtained.

20 g. of the foregoing compound in 12 m1. of benzene, 1 ml. of triton B(benzyltrimethylammonium hydroxide, Midwest Laboratories Inc.) and 1.2m1. of t'butylhydroperoxide (Lucidol Division, Wallace and Tiernan,Inc.) were reacted at room temperature overnight. The mixture was thendiluted with 11% hydrochloric acid, saturated with sodium chloride andextracted repeatedly with ether. The combined extracts were washed withwater to neutral, dried over anhydrous sodium sulfate and evaporated todryness. By crystallization [from acetone hexane, 3,8-acetoxy-l3-hydroxy-20-keto- 1 6a,17a-0xido-l1,13-seco-5u-pregnan-1l-oic-acid-l1,13 lactone was obtained.

'14 g. of the foregoing oxido-compound in 160 ml. of glacial acetic acidwas treated with 30 ml. of acetic acid saturated with dry hydrogenbromide, stirring at room temperature for 1.15 hours. The mixture wasthen diluted with ice water and the bromohydrin which precipitated wascollected by filtration, washed with water and refluxed with 100 g. ofRaney nickel in 1 liter of acetone for 5 minutes. The nickel was removedby filtration, the filtrate was evaporated to dryness and the residuecrystallized from acetone-hexane, thus furnishing3,8-aoetoxy-13,17u-dilhydroxy-20-keto-l 1,13-seco- 5a-pregnand1-oic acid111,13-1actone.

The 3-acetoxy group of the foregoing compound was hydrolyzed by treatinga solution of 10- g. of said compound with 5 00 ml. of methanol,saturated with hydrogen chloride, at room temperature for 0.5 hour.Subsequent dilution with water and collection of the precipitate byfiltration, finally water-washing, drying and recrystallization fromacetone, afforded 3B-13,17ot-trihydroxy-20-keto-11,13-seco-5ot-pregnan11 oic acid 11,13- lac tone.

A mixture of 8 g. of the foregoing compound and 600 ml. of chloroformwas treated under stirring with a chloroform solution containing 1.1molar equivalents of bromine; the bromine solution was added in thecourse of 1 hour and maintaining a temperature below 20 C. The mixturewas then stirred for 20 minutes: more, washed with saturated aqueoussodium bicarbonate solution and then with water, dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure, ina water-bath, at a temperature below 40 C. Thus was obtained21-bromo-3,8,l3,l7a-trihydroxy-20-keto 11,13- seco-5a-pregnan-l l-oicacid 1l-l3-1actone, which was used for the next step without furtherpurification.

The above bromo-compound was dissolved in 16001111. of acetone, mixedwith 6 g. of sodium iodide and refluxed for 2. hours; at the end of thistime g. of anhydrous potassium acetate were added and the mixture wasrefluxed for 40 additional hours.

After concentrating the mixture to small volume under reduced pressure,it was diluted with water and extracted with several portions of ethylacetate. The combined extracts were washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. The residuecrystallized from acetone-hexane, yielding 3B,13,17a,2l-tetra. hydroxy20 keto-ll,l3-seco-5a-pregnan-ll-oic acid-ll, l3-lactone 21-acetate.

To a solution of 4 g. of the above compound in 200 ml. of acetone,cooled in an ice-bath was added a solution of 8 N chromic acid, preparedin dilute sulfuric acid, little by little, while stirring and under anatmosphere of nitrogen, until the color of chromium trioxide persistedin the mixture, which was then stirred for 5 minutes longer. The productwas precipitated by addition of water, collected by filtration,water-washed, dried and crystallized from acetone-hexane. Thus13,l7u,21-trihydroxy- 3,20-diketo-l1,l3-seco-5a-pregnan-ll-oic acid11,13-lactone-21-acetate was obtained.

To a mixture of 12 ml. of anhydrous tetrahydrofuran and 2 m1. of glacialacetic acid were added 2 g. of the above steroid and the mixture wasthen treated with a few drops of a saturated solution of dry hydrogenbromide in glacial acetic acid at room temperature and while stirring.There were then added little by little, 2.1 molecular equivalents ofbromine, stirring the mixture and maintaining its temperature below 20C. After the addition of the bromine was complete, stirring wascontinued for 10 minutes, the product precipitated by addition of Water,collected by filtration, washed with water and dried in vacuo. Thuscrude 2a,4a-dibromo-l3,l7a,21-trihydroxy-3,20-diket0-l1,13-seco-5a-pregnen-ll-oic acid 11,13-lactone 21-acetatewas produced.

To a suspension of 4 g. of calcium carbonate in 40 ml. ofdimethylacetamide, heated almost to the boiling point, was added asolution of 2 g. of the above dibromo-compound in 10 ml. ofdimethylacetamide. The mixture was refluxed for 1 hour, cooled, filteredand the solvent was evaporated under reduced pressure. Upon triturationwith dilute hydrochloric acid there was obtained a crystalline solid,which was collected, washed with water, dried and crystallized frommethanol. Thus 13,17u,2l-trihydroxy-3,20-diketo 11,13 seco-A-pregnadien-1l-oicacid 11,13-lactone 21-acetate was obtained.

Example II To a solution of 0.67 g. of bromine in 20 ml. of acetone(prepared by adding the bromine little by little and waiting untildecolorization before each addition), cooled at 0 C., was added 1.8 g.of sodium carbonate, the mixture was then stirred for 25 minutes at 0C., filtered and to the filtrate was added 8 -g. of sodium iodidedissolved in 400 ml. of acetone. The mixture was refluxed for 45 minutesfurther and cooled.

To the above solution were added 3.5 g. of20,4a-dibromo-13,17u,2l-trihydroxy-3,20-diketo-11,13 seco 5'0:-pregnan-ll-oic acid 11,13-lactone 21-acetate and the mixture wasrefluxed for 5 hours. 3.5 g. of oxalic acid were from methanol.

A mixture of 1 g. of the above compound, 50 ml. of tbutanol, 500 mg. ofselenium dioxide and a few drops of pyridine was refluxed under anatmosphere of nitrogen for 2 days. It was then filtered through celite,the filtrate was evaporated to dryness under reduced pressure and theresidue was triturated with water to give a solid which was collected byfiltration, Washed with water, dried and purified by chromatography onsilica gel. By elution with benzene-ether there were obtainedcrystalline fractions, which were further purified by recrystallizationfrom ethyl acetate in the presence of decolorizing charcoal and finallyby recrystallization from methanol. Thus was obtained13,17,21-trihydroxy-3,20-diketo-11, 13-seco Apregnadien-l1-oic-acid-11,13-lactone 21- acetate, identical with thefinal compound of the preceding example.

Example III A mixture of 1 g. of 13,l7a,21-trihydroxy-3,ZO-diketo-11,13-seco-'a-pregnan-1l-oic acid 11,13;lactone 21-acetate (compareExample I), 50 ml. of t-butanol, 1 g. of selenium dioxide and a fewdrops of pyridine was refiuxed under an atmosphere of nitrogen for 4-days; the product was elaborated as described for the seleniumdioxideoxidation in Example 1. Thus13,17a,21-trihydroxy-3,2O-diketo-11,13-seco-A -pregnadien 11 oicacidl1,13-lactone 21-acetate was produced.

Example IV A suspension of 1 g. of13,17u,21-trihydroxy-3,20-diketo-l1,13-seco-A -pregnen-1l-oic-acid21-acetate (cf. Example I) in 40 ml. of 0.27 N methanolic perchloricacid (prepared by mixing 39 ml. of methanol With 1 ml. of 72% perchloricacid) Was shaken. at room temperature for 20 hours. The resultingsolution was diluted with water, left 2 hours in the refrigerator andthe precipitate was collected by filtration, water-washed, dried andrecrystallized from ethanol, affording 13,17a,21-trihydroxy-3,20-diketo-11,13-seco-A -pregnen-1l-oic acid 11,13-lactone.

Example V Exactly as described in the foregoing example, 13,17 04,2l-trihydroxy 3,20 diketo-11,13-seco-A -pregnadienll-oic-acid11,13-lactone 21-acetate was converted to 13, 17a,2l trihydroxy 3,20diketo-1l,13-seco-A -pregnadien-l l-oic-acid 11,13-lactone.

Example VI A mixture of 1 g. of 13,17oz,21-t1ll1Yd10XY-3,20-dik6t0-11,13 seco-M-pregnen-ll-oic-acid 11,13-l-actone (Examp le IV), 5 ml. ofpyridine and 2 ml. of propionic anhydride was left at roomtemperatureovernight, then poured into water, the mixture heated for half an houron the steambath, then cooled, the solid collected by filtration, washedwith water, dried and purified by crystallizationfrorn acetone-hexane.Thus 13,17oc,21 trihydroxy 3,20-diketo- 11,l3-seco-A-pregnen-1l-oic-acid 11,13-lactone 21-propionate was obtained.

Example VII By a procedure similar to that described in the foregoingexample using the respective acid anhydride or chloride in pyridine,several 21-esters of 13,17 a,21-trihydroxy 3,20 diketo-11,13-seco-A-pregnen-1l-oic acid 11,13-lactone (Example IV) and ofl3,l7oc,2l-trihydroxy 3,20-diketo-11,13-seco-A -pregnadien-1 l-oic-acid11,13-lactone (Example V) were prepared, more particularly the21-cyclopentylpropionate and the benzoate of 13,17 ot,21trihydroxy-3,2O-diketo-11,13-seco A -pregnenll-oic-acid 11,13-lactoneand of 13,17a,2l-trihydroxy-3, 20 diketo-11,13-seco-A-pregnadien-1l-oic-acid 11,13- lactone, and the 21-propionate of13,l7a,21-trihydroxy-3, ZO-diketo-l1,13-seco-A -pregnadien 11 oic acid11, 13-lactone.

I claim:

1. A compound of the following formula:

CHlOR wherein R is selected from the group consisting of hydrogen andhydrocarbon carboxylic acyl of less than 12 carbon atoms.

2. 13,17a,21-trihydroxy-3,20 diketo 11,13 seco-A pregnen-l l-oic-acid11,13-lactone.

3. The C-21-hydrocarbon carboxylic acid ester of less than 12 carbonatoms of 13, l7u,2l-trihydroxy-3,20- diketo-11,13-seco-A-pregnen-1l-oic-acid 11,13-lactone.

4. 13,17a,21 trihydroxy 3,20 diketo 11,13 seco- A -pregnen-11-oic-acid11,13-1actone 21-acetate.

5. 13,17a,2l trihydroxy 3,20 diketo-11,13-seco-A pregnen-l l-oic-acid11,13-lactone 21-propionate.

6. 13,17a,21 trihydroxy 3,20 diketo 11,13 seco- M-pregnen-ll-oic acid11,13-lactone 21-cyclopentylpropionate.

7. A compound of the follownig formula:

CHnOR wherein R is selected from the group consisting of hydrogen andhydrocarbon carboxylic acyl or" less than 12-carbon atoms.

8. 13,170:,21-tlil1YCll'0XY-3,2Odik6t0-11,13 -seco A pregnadien-l l-oicacid-11,13-lactone.

9. The C-21-hydrocarbon carboxylic acid ester of less than 12 carbonatoms of 13,17a,2l-trihydroxy-3,20-dikcto-l 1,13-sec0-A -pregnadien-1l-oic acid-1 1,13-lactone.

10. 13,17a,21 trihydroxy-3,20-diketo-11,13-seco-A pregnadien-11-oicacid-11,13-lactone 21-acetate.

11. 13,17a,21-trihydroxy-3,20-diketo-11,13-seco A pregnadien-ll-oic-acid 11,13-lactone 21-propionate.

12. l3,17a,21 --trihydroxy 3,20 diketo 11,13 seco- A -pregnadien-l1-oicacid 11,13-lactone 21-cyclopentylpropionate.

13. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen andhydrocarbon car-boxylic acyl of less than 12 car bon atoms.

14. 13,l7a,21 trihydroxy 3,20-diketo-11,13-seco-5apregnan-ll-oic acid11,13-lactone 21-acetate.

15. A compound of the following formula:

CHzOR wherein R is selected from the group consisting of hydrogen andhydrocarbon carboxylic acyl of less than 12 carbon atoms.

16. 35,13,1701,2l-tetrahydroxy-ZO-keto-11,l3-seco 5apregnan-ll-oic acid11, 13-lactone ZI-acetate.

17. A compound of the following formula:

10 wherein R is selected from the group consisting of hydrogen andhydrocarbon carboxylic acyl of less than 12 carbon atoms.

18. 35,13,17a-trihydroxy 20 keto 11,13 seco 5apregnan-ll-oic acid11,13-lactone.

19. 35,13,170; trihydroxy-ZO-keto-I1,13-seco-5wpregnan-ll-oic acid11,13-'lact0ne 3aacetate.

20. A compound of the following formula:

References Cited in the file of this patent Rothman et al.: Jour. Amer.Chem. 800., volume 76 (1954), pages 527-532.

1. A COMPOUND OF THE FOLLOWING FORMULA: